Oral compositions for calculus retardation

ABSTRACT

ORAL COMPOSITIONS, SUCH AS TOOTHPASTE, MOUTHWASH, AND THE LIKE, CONTAINING CERTAIN PERFLUORO-1,2-DIPHOSPHONOCYCLOALK-1,2-ENES AND SALTS THEREOF, WHICH RETARD DENTAL CALCULUS FORMATION WITHOUT DAMAGING TOOTH STRUCTURE.

U S a e Pate s "w 16 claims No Drawing. Filed Dec. 11, 1967, Ser."- Int.Cl. A61k 7/16 U.S. 01.424-52 ABSTRACT OF THE DISCLOSURE j Oralcompositions,'such as,toothpaste, mouthwash, and the like, containingcertain perfluoro-1,2-dipliosphonocycloalk-1,2-enes and salts thereof,which retard dental calculus formation without damaging tooth structure.

BACKGROUND OF THE INVENTION 3,584,116 Patented June 8, 1971calcification. Thus, the development of oral .compositions whicheffectively retard calculus calcium chelation has been impeded by safetyconsiderations. Safe and effective anticalculus agents have beendeveloped (see. for example US. application Ser. No. 668,702, filedSept. '18, ,1967, by Homer W :McCune .and Nathaniel .B. Tucker), nowabandoned, however, researcherscontinueto seek alternative anticalculusagents for use in oral compositions.

SUMMARY OF THE INVENTION It has now been discovered that certainperfluoro-L2} diphosphonocycloalk-l,2-enes and salts thereof (some-Dental calculus, or tartar as it is sometimes called, is

a deposit which forms on the surfaces of the teeth at the gingivalmargin. Supragingival calculus appears principally in the areas near theorifices of the salivary ducts; e.g., on the lingual surfaces of thelower anterior teeth and on the buccal surfaces of the upper first andsecond molars, and on the distal surfaces of the posterior molars.

Mature calculus consists of an inorganic portion which is largelycalcium phosphate arranged in a hydroxylapatite crystal latticestructure similar to bone, enamel and dentine. An organic portion isalso present and may consist of desquamated epithelial cells,leukocytes, salivary sediment, food debris and various types ofmicroorganisms.

As the mature calculus develops, it becomes visibly white or yellowishin color unless stained or discolored by some extraneous agency. Inaddition to being unsightly and undesirable from an aestheticstandpoint, the mature calculus deposits are constant sources ofirritation of the gingiva and thereby are a contributing factor togingivitis and other diseases of the supporting structures of the teeth,the irritation caused by deposits of calculus decreasing the resistanceof tissues to endogenous and exogenous organisms.

A wide variety of chemical and biological agents have been suggested inthe art to retard calculus formation or to remove calculus after it isformed. Mechanical removal of this material periodically by the dentistis, of course, routine dental office procedure.

The chemical approach to calculus inhibition generally involveschelation of calcium ion which prevents the calculus from forming and/orbreaks down' mature calculus by removing calcium. A number of chelatingagents have been employed for this purpose. See, forexample, BritishPat. 490,384, granted Feb. 15, 1937, which discloses oral compositionscontaining ethylenediaminetetraacetic acid, and related polycarboxylicacids as anticalculus agents; German Auslegeschrift 1,149,138, publishedMay 22, 1963, which discloses certain watersoluble diglycolates asanticalculus agents; and U.S. Pat 1,516,206 which discloses oralcompositions containing various sugar lactones for this purpose.

Although certain of the art-disclosed chelators are pur- I timesreferredv to collectively hereinafter ,as PFDC) possess the surprisingcapacityto retard the development of dental calculus without removingcalcium from dental enamel or otherwise damaging the tooth structurewhen employed in oral compositions maintained within defined AlthoughPFDC possess only nominal calcium sequestering capacities in the pHrange characteristic or oral compositions, they effectively retardcalculus formation by a mechanism that is believed to involve theinhibition of hydroxylapatite crystal growth as will be discussed morefully hereinafter.

Unlike irorganic polyphosphates such as pyrophosphates, the PFDC resisthydrolysis in aqueous products and therefore remain in an active formthroughout the normal shelf-like of such products.

It is therefore an object of this invention to provide novel oralcompositions which retard the formation of calculus without otherwiseaffecting the tooth structure.

It is another object of this invention to provide an improvide methodfor retarding the development of dental calculus.

Other objects will become apparent from the following detaileddescription.

DETAILED DESCRIPTION OF THE INVENTION This invention is an oralcomposition effective in inhibiting the formation of dental calculuswithout adversely affecting the tooth structure comprising from about0.01% to about 10% by weight of at least one anticalculus agent selectedfrom the group consisting of those of the structural formula:

CPO3M2 2)n --CPO Mz wherein n is an integer from 2 to 4 and M ishydrogen or a pharmaceutically acceptable salt forming cation such asalkali metal (e.g., sodium and potassium), alkaline earth metal (e.g.,calcium and magnesium), stannous, indium, ammonium, or low molecularweight substituted ammonium e.g., mono-, di-, and triethanol-ammonium);the pH of the composition being within the range from about 5.0 to about11.0.

PFDC can be prepared by any suitable method, however, an especiallypreferred method involves reacting trialkyl phosphites with1,2-dichloroperfluorocycloalkenes in accordance with the proceduresfully described by Frank in J. Org. Chem., 30, 3663 (1965), andhydrolyzing the resulting esters.

. The concentration of PFDC in the oral compositions of this inventioncan range from about 0.01% to about 10% by weight. Oral compositionswhich in the ordinary course of usage are likely to be accident-allyingested in substantial volumes should contain lower concentrations ofPFDC. Thus, a mouthwash in accordance with this invention preferablycontains less than about 3% by weight of PFDC. Dentifrice compositionsand topical solutions, the latter to be administered professionally, cancontain up to about 10% by weight, preferably from about 0.1% to about5.0% by weight of PFDC.

The pH of the compositions of this invention can range from about 5.0 toabout 11. Below about pH 5.0 damage to the dental enamel can occur inspite of the relatives safety of the PFDC. Above about pH 11.0difficulty is encountered in formulating products having satisfactoryflavor, mildness, and safety. A preferred pH range is from about 6.5 toabout 10. The pH of the composition, of course, is determinative of thepredominant salt form of the PFDC present therein.

While it is not intended that this invention be limited by a particulartheory of operation, it has been observed that PFDC interfere with theprogress of calculus formation by interfering with the conversion ofamorphous calcium phosphate to crystalline calcium hydroxylapatite.Amounts of PFDC which are much too small to chelate any appreciablequantities of calcium have been found to retard the formation of calciumhydroxylapatite. This selective action on the formative calculusdeposits without demineralizing action on the dental enamel issurprising.

The eflicacy of the compositions of this invention in calculusprophylaxis was demonstrated by the Crystal Growth Inhibition test whichwas conducted as follows:

CRYSTAL GROWTH INHIBITION DETERMINATION As hereinbefore stated, the PFDCinhibit the growth of calcium hydroxylapatite crystals and in this wayinterfere with the normal formation of calcium hydroxylapatite fromsolution. This test is to determine the effect of PFDC on the calciumphosphate formed on addition of calcium ion to orthophosphate ion atconstant pH. The procedure is as follows using a representative PFDCcompound as an example:

1 ml. of a 0.1 M stock solution of NaH PO -H O is diluted with 22 ml. ofdistilled water. 1 ml. of an aqueous solution of disodium3,4,5-hexafiuor-1,2-diphosph0nocyclopent-1,2-ene (HFDC) at aconcentration sufficient to provide the desired ultimate concentrationin the reaction mixture is added to the diluted NaH PO solution and thesolution is adjusted to pH 7.4 with sodium hydroxide. To this solutionis added 1 ml. of a 0.1 M solution of CaCl -2H O preadjusted to pH 7.4with sodium hydroxide. This mixture is held at a constant pH 7.4throughout the reaction period.

After a sufficient reaction time as determined by the operator,generally within 90 minutes, the solution is filtered through a 0.45p.millipore filter pad, dried, and analyzed by X-ray dilfration. The solidcalcium phosphate precipitated from the above-described solution withoutHFDC gives a typical hydroxylapatite pattern, while the calciumphosphate precipitated under the same conditions but in the presence ofsmall amounts of HFDC of this invention is amorphous to X-rays.

Those compounds which are effective in inhibiting the growth ofhydroxylapatite crystals at concentrations of less than 1.5 X M underthe conditions of this test are effective in reducing calculus formationin rats, while several compounds outside the scope of this inventionthat have little or no effect in this test do not reduce calculus inrats.

The concentration of HFDC required to inhibit the formation of calciumhydroxylapatite under the conditions specified above was found to be1.82 10- M. The presence of this concentration of a representative PFDCin the test solutions of the Crystal Inhibition Test results in theprecipitation of an amorphous calcium phosphate rather than crystallinecalcium hydroxylapatite as occurs without HFDC. By way of comparison,ethylenediaminetetraacetic acid and nitrilotriacetic acid which havebeen suggested for use as anticalculus agents in the art fail to inhibitcrystal growth of hydroxylapatite at molar concentrations of 2.45 X 10-and 2.54 10* respectively. At higher concentrations, these prior artcompounds prevent precipitation of calcium phosphate in this testbecause of their removal of calcium ion from solution by their se- 4questering properties, not by their crystal inhibition properties.

The safety of PFDC for use in contact with dental surfaces is determinedby the Continuous Immersion Test conducted as follows: Mature humanteeth are immersed in aqueous solutions or dispersions of oralcompositions containing PFDC in accordance with this inventin at pH 7.0and pH 10.0. Every four hours the teeth are examined fordecalcification. Under visible light, enamel decalcification can bedetected by a loss of inter, while opaque spots or slight surfaceroughtening. The teeth are examined macroscopically and microscopicallyat the end of seven days. If no decalcification is observed through thisperiod, the compositions cause no damage to dental enamel, and areconsidered safe in this respect for use in the oral cavity;

A dentifrice, especially toothpaste, containing PFDC is a preferredembodiment of this invention. Toothpaste compositions conventionallycontain abrasive materials, sudsiug agents, binders, humectants,flavoring and sweetening agents.

The abrasive materials and other adjuncts used in the practice of thisinvention are preferably not sources of much soluble calcium so that thecrystal growth inhibiting capacity of PFDC is not depleted to an extentthat its anticalculus activity is impaired. Thus, conventional abrasivessuch as dicalcium orthophosphate and calcium carbonate are preferablynot used. However, predominantly fl-phase calcium pyrophosphate preparedfor example in accordance with the teachings of Schweizer, US. Pat.3,112,247, granted Nov. 26, 1963, while contains relatively littlesoluble calcium can be used. An especially preferred class of abrasivesfor use herein are the particulate thermosetting polymerized resins asdescribed by Cooley et al. in US. Pat. 3,070,510, granted Dec. 25, 1962.Suitable resins include, for example, melamines, phenolics, ureas,melamine-ureas, melamine-formaldehydes, ureaformaldehyde,melamine-urea-formaldehydes, cross-linked epoxides, and cross-linkedpolyesters.

Other suitable abrasives include alumina and the insoluble non-calciummetaphosphates such as sodium metaphosphate. Mixtures of abrasives canalso be used. In any case, the total amount of abrasive in thedentifrice embodiments of this invention can range from 0.5% to byweight of the dentifrice. Preferably, toothpastes contain from 20% to60% by weight of abrasive. Abrasive particle size preferably ranges from2p to 20,11.

Suitable sudsing agents are those which are reasonably stable and formsuds throughout a wide pH range, preferably nonsoap anionic organicsynthetic detergents. Examples of such agents are water-soluble salts ofalkyl sulfate having from 10 to 18 carbon atoms in the alkyl radical,such as sodium lauryl sulfate; water-soluble salts of sulfonatedmonoglycerides of fatty acids having from 10 to 18 carbon atoms, such assodium monoglyceride sulfonates; salts of C -C fatty acid amides oftaurine, such as sodium N-methyl-N-palmitoyl tauride; salts of C -Cfatty acid esters of isethionic acid; and substantially saturatedaliphatic acyl amides of saturated monoaminocarboxylic acids having 2 to6 carbon atoms and in which the acyl radical contains 12 to 16 carbonatoms, such as sodium N-lauroyl sarcoside. Mixtures of two or moresudsing agents can be used.

The sudsing agent can be present in the dentifrice compositions of thisinvention in an amount from 0.5% to 5% by weight of the totalcompositions.

In preparing toothpastes, it is necessary to add some thickeningmaterial to provide a desirable consistency. Preferred thickening agentsare hydroxyethylcellulose and water-soluble salts of cellulose etherssuch as sodium carboxymethylcellulose and sodiumcarboxymethylhydroxyethylcellulose. Natural gums such as gum karaya, gumarabic, and gum tragacanth can also be used. Colloidal magnesiumaluminum silicate or finely divided silica can be used as part of thethickening agent to further improve texture. Thickening agents in anamount from 0.5% to 5.0% by weight of the total composition can be used.

Melamine/urea/tormaldehyde resin 1 Urea/formaldehyde resin L Sodiummetaphosphate Alumina Z Sodium carboxymethyl celluloseHydroxyethylcellulose Magnesium aluminum silicate Sodium lauryl sulfateSodium coconut monoglyceride sulfonate Saccharin Several mouthwashcompositions are prepared in accordance with this invention as follows:

It is also desirable to include some humectant mate- Parts by weightrial in a toothpaste to keep it from hardening. Suitable 5 Example X XI'ifi humectants include glycerine, sorbitol, and other edible polyhydricalcohols. The humectant can comprise up to 5 1M 10.0 1M m about 3% byweight of the toothpaste composition. yl alco ol 16. 16. 5 16.3 16.15Suitable flavoring agents include oil of Wintergreen, g ;gggfi i i 3,1;oil of peppermint, oil of Spearmint, oil of sassafras, and Sodiumcyclamate- .075 .075 .075 oil of clove. Sweetening agents which can beused include 5533?, 4'??? a??? saccharin, dextrose, levulose and sodiumcyclamate. g g 0 10 0 Several representative oral compositionsillustrating this invention are set forth in the following examples.Polvoxyethylene moles oiethylcne oxide) sorbitan monooleatea 15 ith iflfit fi itislfiiiii lliiffififi EXAMPLE I l I 1 giammonium salt of3,4,5-hexafluor0-lIZ-diphosphonocyclopent- A toothPaste of the followingcomposmon 18 prepared ,4 Tripotassium salt of3,4,5-hexafluoro-1,2-diphosphonocyclopentby conventional methods.1,2-ene.

Parts by Weight 5 Tr1 sod1um salt of3,4,fi-hexafluoro-l,2-d1phosphonocyclopent-l, 2 ene. W t 31 5 8 thAdflustefi to value indicated with the base solution corresponding to a61 2O esa use Srb1t01 When used in the same manner as conventionalmouthsaccllarln wash, at least once daily, each of the abovecompositions Calcwrp Pyrophosphate 39-00 materially reduces accumulationof calculus on the sur- Glyflerlne 18-00 faces of teeth. Nodecalcification is observed after seven g gf alkyl (t l sulgite Ki 25days exposure of dental enamel to these compositions. 0 mm coconu monogyceri e su ona e 7 Sodium carboxymethyl cellulose 1-15 EXAMPLE XIVMangeisium alllmlmlm slllcates Q40 A prophylaxis paste for use by thedentist for removal f j g of stains and polishing the teeth aftermechanical removal 1315051111111 sallt 2 3,4,5'heXafiurliz'dlphosphom" 150 of calculus deposits is formulated as follows:

c co ent- -ene p 530 Parts bywt.

n N va' Prepared in accordance with US. Pat. 3,112,247 granted 2 10pumlce 1 Nov. 26, 1963. 2 5

c r ThlS composition effectively retards calculus formation y 6 me I 7 aHydroxyethylcellulose .22 on dental enamel and when tested in theContinuous Im- Saccharin 33 2 ;;i gg g g sti gzi g no decalclficatlon 18noted Disodium salt of 3,4,5-hexafiuoro-l,Z-diphosphonoy Pcycl0pent-1,2-ene 4.0 Toothpaste compos1t1on substantially identical tothe Trisodium Salt of 3 4 5 h H 12 h composition of Example I areprepared with the dipotas- 40 home do In 12 exa uoro' 1p 4 0 sium saltof 3,4 tetrafluoro-l,Z-diphosphonocyclobut-1,2- f y pe ene, themonocalcium salt of 3,4,5,6 octafiuoro-l,2-dipphosphonocyclohex-l,Z-ene; 3,4 tetrafluoto-LZ-diphos- When applied tothe teeth with a prophylactic rubber phonocyclobut-1,2-ene; 3,4,5,6octafiuoro 1,2-diphoscup in the conventional manner, this compositionhelps phonocyclohex-l,2-ene; and the di(triethanolammonium) retard thedevelopment of new calculus deposits. salt of3,4,5-hexafluoro-l,Z-diphosphonocyclopent-1,2-ene Toothpowders and thelike can be prepared by convenraltherhthan tlie disodium2 saltofd3,4,5-hex:fluoro-1,Z-ditiOnal1 methods and containing, in addition tothe usual p osp onocyc opent l, -ene, a justing t e pH to 5.9. ingreients, an amount of PFDC within the ranges speci- These compositionssubstantially retard calculus formafied herein, to provide an effectivemeans of retarding no; atrlild do no; defiatlcifty1 detntal enamtelw dcalTc Elus formation ttivithcilut dimagglfgDtlg tolgtli1 structure. orer examp es 0 0o pas e composl ions in accor ose componen s ot er t an w1c were inance with the invention are set forth in Table 1 below. cludedin the foregoing examples and various mixtures of TABLE 1 Parts byweight Example II III IV V VI VII VIII IX Component:

Flavoring Diammonlum salt of3,4,5-hexafiuoro-l,2-diphosphonocyclopent-1,Z-ene. Monocalclum salt of3,4-tetrafiuoro-l,2-diphosphonocyclobut-l,2-ene- Distannous salt of3,e-tetrafluoro-l,2-diphosphonocyclobut-1,2-ene Indium salt of3,4-tetrafluoro-1,2-diphosphonocyclobut-l,2-ene Triammonium salt of3,4-tetrafiuoro-1,2-diphosphonocyclobut-l,2'ene Trisodium salt of3,4,5,fi-octafluoro l,2-diphosphonocyclohex-1,2-ene Distannous salt of3,4,5,6-octafiuoro-l,2-diphosphonocyclohex-1,2-ene a lege(diethanolammonium) salt of3,4,5,6-octafluoro-l,2-diphosphonocyclohex-1,2-ene a er Adjust pH to 5.5

As described in U.S. Pat. 3,070,510. 9 Prepared in accordance with U.S.Pat. 3,003,919.

Balance 6. 5 7. 0

those components are illustrative of carriers suitable for use in theoral cavity.

In reference to pH adjustments in the foregoing examples, it is to beunderstood that a base of a cation corresponding to the salt form of thePFDC employed is used. In each case in which the PFDC was added in itsacid form to the example compositions, the pH was adjusted to thespecified value with NaOH. Adjustments in pH to more acid levels whenadding the PFDC in the salt forms is accomplished with HCI. It will beobvious to those skilled in the art that pH adjustments can be made withany acid or base suitable for use in the oral cavity.

What is claimed is:

1. A method for inhibiting the formation of dental calculus withoutadversely afiecting tooth structure, comprising the application todental surfaces of a composition comprising from about 0.1% to about5.0% by weight of an anticalculus agent selected from the groupconsisting of those of the formula:

wherein n is an integer from 2 to 4 and the pharmaceutically acceptablesalts thereof, and a carrier suitable for use in the oral cavity, the pHof the composition being within the range from about 5 .0 to about 11.0.

2. The method of claim 1 wherein the anticalculus agent is3,4,5-hexafluoro-1,2-diphosphonocyclopent-1,2- ene or an alkali metal,alkaline earth metal, stannous, indium, ammonium, or low molecularweight substituted ammonium salt thereof.

3. In a dentifrice composition containing from about 5% to about 95% byweight of a dentifrice abrasive and having a pH within the range fromabout 5.0 to about 11.0, the improvement comprising the incorporationtherein of from about 0.1% to about 5.0% by weight of an anticalculusagent selected from the group consisting of those of the formula:

-CPO3Hz wherein n is an integer from 2 to 4 and the pharmaceuticallyacceptable salts thereof.

4. The. composition of claim 3 wherein the anticalculus agent is3,4,5-hexafiuoro-1,Z-diphosphonocyclopent-1,2- ene, or an alkali metal,alkaline earth metal, stannous, indium, ammonium or loW molecular weightsubstituted ammonium salt thereof.

5.1 In a mouth ash composition containing a flavoring agent and having apH within the range from about 5 .0 to about 11.0, the improvementcomprising the incorporation therein of from about 0.1% to about 5.0% byweight of an anticalculus agent selected from the group consisting ofthose of the formula:

|-'--CP 03H: 2)n ll 1 fif wherein n is an integer from 2 to 4 and thepharmacew tically acceptable salts thereof. p

6. The composition of claim 5 wherein the anticalculus agent is 3,4,5hexafluoro-l,2-diphosphonocyclopent 1,2- ene or an alkali metal,alkaline earth metal, stannous, indium, ammonium, or low molecularweight substituted ammonium salt thereof;

' References Cited Frank, Journal of Organic Chemistry, vol. 31, pp.1521 1524, May 1966. Copy in POSL. 1 Hoffman et al., Journal ofPeriodontology, vol. 34,.p. 44, July 1963. M V v RICHARD LI'HUFF,Primary Examiner

